Dear Editor, Genetic defects of mitochondrial respiratory chain (RC) form an expanding family of rare diseases, whose number and global incidence increase constantly, whereas treatment options remain extremely limited. In line with recent literature data (Bastin et al., 2008) suggesting a potential of bezafibrate for correction of RC defects in human fibroblasts, Viscomi et al. recently published inCell Metabolism the results of in vivo experiments aimed at evaluating the effects of bezafibrate in RC-deficient knockout mice (Viscomi et al., 2011). The conclusions from this study appeared in marked contrast with those drawn from in vitro studies in patient cells and apparently cast doubt on therapeutic properties of bezafibrate in RC deficiencies. However, we consider that limitations in the study design could explain the apparent inefficacy and toxic effects of bezafibrate reported by the authors. Furthermore, based on clinical data obtained in individuals treated with bezafibrate, we present data showing that this drug can stimulate the RC function in the human skeletal muscle. One of the most questionable points in the study of Viscomi et al.(2011) is the bezafibrate dosage tested in the knockout mice (0.5% drug added to standard diet for 1 month), for several reasons. At first, when using this diet, it is easy to calculate that the daily drug supply is in considerable excess compared to the pharmacological dose used in humans. Indeed, assuming a mouse body weight of 25–30 g and a 4 g/day food intake, 0.5% bezafibrate in chow is equivalent to 666–800 mg/kg/day bezafibrate, ie, represents up to 80-fold the dose used for the treatment of dyslipidemia (10 mg/kg/day). The second and main concern is the known toxicity and carcinogenic potential of such high doses of fibrate in rodents, established in the early 1980s. Indeed, it is known that a 2-fold increase in liver weight is already observed in mice after 1 week on a diet containing 0.5% bezafibrate, likely due to PPAR-a-mediated induction of genes involved in hepatocyte proliferation (cyclin D1, CDK4, and c-Myc), whereas mice kept on this regimen will develop hepatocarcinoma in the long term (Hays et al., 2005). Importantly, recent studies also show that clinically relevant doses of bezafibrate elicit triglyceride-lowering effects in mice, and no toxic effects (Nakajima et al., 2009). Taking into account these literature data, there is no rationale to use 0.5% bezafibrate in diet when investigating pharmacological properties of this drug. Furthermore, it appears likely that liver hepatomegaly reported both in treated Surf 1À/À and wildtype animals reflects a classical toxic response to high doses of bezafibrate. PPAR agonists at high doses can also induce muscle damages (myofibril degeneration and inflammatory cell infiltration). Accordingly, worsening of muscle damages in ACTA-Cox15À/À mice treated by bezafibrate could also be ascribed to toxic effects of bezafibrate overdosage. Under these conditions, conclusions on the therapeutic potential of bezafibrate in RC-deficient mouse models cannot be drawn, and extrapolation to the treatment of RC-deficient patients appears irrelevant. Importantly, the hepatotoxicity and carcinogenic activity of fibrates are clearly rodent specific. Indeed, it has long been known that humans are resistant to the development of hepatocarcinoma after chronic exposure to fibrates, and largescale studies performed since the 1980s consistently established that bezafibrate is a safe drug, with limited side effects (Tenenbaum et al., 2005, cited in Bonnefont et al., 2010).

Regarding the possible use of this drug in patients with inborn metabolic myopathies, we tested bezafibrate in patients with the …